CLINICAL REVIEW Hereditary Hemochromatosis J Am Board Fam Pract: first published as on 1 July 2001. Downloaded from

Robert B. Hash, MD

Background: The understanding of hereditary hemochromatosis, along with the availability of , is changing the approach to diagnosis of the disease. Methods: A MEDLINE search was performed using multiple key words related to hemochromatosis and metabolism. Results: Most cases of hereditary hemochromatosis are caused by a single to the HFE gene, resulting in unregulated dietary iron uptake. The of hereditary hemochromatosis are nonspecific and common in family practice settings. Measuring the saturation level is a cost-effective way to screen for suspected disease. Subsequent workup includes serum levels, hepatic enzyme levels, and HFE gene testing, or biopsy. HFE gene testing can provide a definitive diagnosis in many patients. Liver biopsy is useful and indicated when liver disease is clinically evident. Conclusion: For many patients, hereditary hemochromatosis can be diagnosed and treated in the physician’s office. After iron mobilization with therapeutic phlebotomy, most patients will require phle- botomy 2 to 4 times each year throughout their lifetime. Treatment before organ toxicity occurs leads to a normal life span. Treatment after symptoms appear is less effective but can improve some signs and symptoms of iron toxicity.(J Am Board Fam Pract 2001;14:266–73.)

Hereditary hemochromatosis is thought to be the Methods most common inherited disorder in whites, and A MEDLINE search was performed using multiple

perhaps the most common classically inherited dis- key words related to hemochromatosis and iron http://www.jabfm.org/ ease in America. This disorder is most commonly metabolism. found in persons of northern European descent, whereas it rarely occurs in Africans or Asians.1 The occurrence of the disease in Hispanics can be sim- Defining the Disease ilar to that in whites.1,2 It is estimated that approx- Hereditary hemochromatosis has been traditionally imately 1 in 200 whites in the United States are defined as an inherited disorder characterized by on 24 September 2021 by guest. Protected copyright. homozygous for the gene thought to be responsible inappropriately high absorption of dietary iron, for the disease,1,3 although the frequency has been which leads to abnormal accumulation of iron in 2,3 reported to be as high as 1 in 150 in some popula- parenchymal organs. In 1996, the HFE gene was tions.4 Approximately 25% of the men and 50% of isolated on chromosome 6. Since this finding he- the women with hereditary hemochromatosis will reditary hemochromatosis has been defined by develop life-threatening consequences of the dis- some as the presence of a homozygous defect in the 3,5 HFE gene with direct or indirect evidence of iron ease in their lifetime. Studies suggest that the overload.8 The requirement for evidence of iron disease has been underdiagnosed, with considerable overload to establish the diagnosis is a point of resultant reduction in both quality and quantity of controversy in the new era of genetic testing.3,6,9–12 life.5–7 For this article, hereditary hemochromatosis will be defined as the phenotypic expression of in the presence of the HFE known to cause the disease. Iron overload is not synonymous with hereditary Submitted, revised 29 December 2000. From the Department of Family Medicine, Mercer Uni- hemochromatosis. Although hemochromatosis is versity School of Medicine, Macon, Ga. Address reprint the most common cause of primary iron overload, requests to Robert B. Hash, MD, Department of Family Medicine, Mercer University School of Medicine, 1550 Col- there are other inheritable causes of primary iron lege St, Macon, GA 31207. overload, some of which occur only in the setting of

266 JABFP July–August 2001 Vol. 14 No. 4 Table 1. Classification of Iron Overload of iron absorption by decreasing the affinity of the 15,16 Types of Iron Overload Cause transferrin receptor for transferrin HFE pro- tein production is regulated in response to iron J Am Board Fam Pract: first published as on 1 July 2001. Downloaded from Primary Iron Overload stores by an unknown mechanism. Iron regulatory HFE gene mutation- C282Y homozygotes proteins or a number of other proteins known to be associated hemochromatosis C282Y simple involved in cellular iron metabolism might be in- (hereditary hemochromatosis) heterozygotes 17 H63D homozygotes volved. Compound heterozygotes Pathophysiology and Genetics of Hereditary Non-HFE-associated Autosomal dominant hemochromatosis (South Pacific region) Hemochromatosis Sporadic familial clusters The clinical disease of hereditary hemochromatosis Nonhereditary is usually caused by a homozygous autosomal re- cessive mutation in the HFE gene. In approxi- mately 60% to 90% of cases, the defect is a single Atransferrinemia missense mutation at position 282 where cysteine is replaced by tyrosine (C282Y).1,18,19 The C282Y Friedreich ataxia mutant HFE protein is unable to bind to beta2- Secondary iron overload and Ineffective erythropoiesis microglobulin, with the result being unregulated miscellaneous causes Chronic (thalassemia major, transferrin receptor-mediated iron uptake in the sideroblastic ) gut.20,21 Multiple transfusions The prevalence of the homozygous C282Y mu- Primary liver diseases tation ranges from 1 in 200 for whites to 1 in 4,000 Porphyria cutanea tarda for those of African-American heritage. There ap- Iatrogenic (parenteral or pears to be variable expression of iron overload in oral) Chronic hemodialysis persons with the homozygous C282Y mutation,

with as many as 30% to 50% of those homozygous http://www.jabfm.org/ for the defect showing no signs of phenotypic ex- pression at the time of discovery.2,22,23 As much as excessive iron intake. Table 1 displays the differen- 10% of the US white population is heterozygous tial diagnosis of iron overload. for the C282Y mutation.18,24 Persons affected with hereditary hemochroma- Physiology of Iron Absorption tosis absorb 3 to 4 mg/d of iron, instead of the on 24 September 2021 by guest. Protected copyright. Most Americans ingest approximately 15 to 20 mg normal 1 to 2 mg/d. The net result is a positive iron of elemental iron daily. Of this amount, only about balance in the range of 400 to 1,000 mg/y.1 Ninety 1 to 2 mg are actually absorbed in the gut. For percent of the excess iron stores are retained in the those with normal iron metabolism, daily loss of liver.9 As ferrous iron accumulates in the parenchy- iron (menstrual losses, stool, and sweat) roughly mal tissues, the intracellular iron-binding sites are equals absorption.13,14 Because humans have no overwhelmed, which results in lipid peroxidation, physiologic mechanism to alter iron excretion to cellular injury, and fibrosis.1,2 meet demand or availability, iron balance in the In addition to the mutation at the 282 position, normal state is maintained through mechanisms a second mutation has been found at position 63, that control absorption.13 Ferrous iron in the gut is where histidine is replaced by aspartate (H63D). then actively transported into the enterocyte and The H63D mutation, while able to bind to trans- stored in the form of ferritin. Enterocyte absorp- ferrin receptors, appears to lack the normal high tion of iron is reduced by recent high dietary iron degree of inhibitory effect on the transferrin recep- intake, by increased transferrin saturation, and by a tor.2,17 Persons homozygous for the H63D muta- yet-to-be-determined erythropoietic regulator from tion and those who are compound heterozygotes the marrow.13 (with the C282Y mutation) have a low rate of phe- The HFE gene product, the HFE protein, binds notypic expression, accounting for approximately to beta2-microglobulin at the cell in a transmem- 5% and 15% cases of hereditary hemochromatosis, brane configuration8 and acts as a major regulator respectively.5,25

Hereditary Hemochromatosis 267 Physical Findings and Symptoms of Other endocrine abnormalities in patients with Hemochromatosis hereditary hemochromatosis can result from hypo- J Am Board Fam Pract: first published as on 1 July 2001. Downloaded from The symptoms and signs in patients with symptom- thalamic dysfunction or glandular involvement or atic hemochromatosis are very common in the fam- both. For example, testicular atrophy is due both to ily practice setting. Common symptoms include testicular fibrosis and decreased gonadotropin pro- weakness, fatigue, arthralgias and arthritis, inter- duction. gland involvement is manifest by mittent abdominal pain, loss of libido, and impo- thyroid tissue inflammation and fibrosis, with ini- tence.18 The most common symptoms are arthral- tial hyperthyroid function followed by low thyroid 26,32 5 output. gias and fatigue. Physical and laboratory findings The arthritis seen with hereditary hemochroma- include skin hyperpigmentation, hepatomegaly, ev- tosis mimics osteoarthritis clinically and radio- idence of failure, testicular atrophy, elevated graphically. The metacarpophalangeal and the liver enzymes, hyperglycemia, low testosterone lev- proximal interphalangeal joints of the hands are els, and hypothyroidism. The symptoms usually usually affected first, followed by the large joints of begin to appear in the third to sixth decade of life. the lower extremities and spine.26,33 Symptoms appear, on average, 10 to 15 years ear- lier in men, presumably because women lose iron during menstruation and pregnancy in the repro- Diagnosis 6 ductive years. The classic triad of skin bronzing, Considering how commonly the above signs and cirrhosis, and diabetes is found in only a small symptoms occur in typical primary care practice, a 1,7 percentage of patients at the time of diagnosis. low-cost method to evaluate for hereditary hemo- Hepatic involvement manifested by elevated chromatosis is essential. Screening for hemochro- liver enzymes occurs in up to 65% of affected matosis has resulted in earlier diagnosis. In some patients at the time of diagnosis.26 The expression studies 75% of new cases are diagnosed during the and severity of hepatic disease is dependent on clinically asymptomatic stage of the disease.8,18 concurrent toxins, such as alcohol, viruses, and Figure 1 displays an algorithm for the evaluation of http://www.jabfm.org/ medications. Hepatic fibrosis eventually leads to patients with suspected hereditary hemochromato- cirrhosis in many untreated patients.5 The hepatic sis. fibrosis resulting from hereditary hemochromatosis When clinical findings warrant evaluation, the is a causative factor in approximately 3% of cases of best phenotypic screening tool is the serum trans- 5,9–11,34 hepatic cirrhosis27,28 and 10% to 30% of cases of ferrin saturation. A newer test, the unsatur- 29 ated iron-binding capacity, shows promise as a hepatocellular carcinoma. on 24 September 2021 by guest. Protected copyright. Cardiac involvement occurs in 5% to 50% of the more cost-effective screening test for the general 10,34 cases. Diastolic dysfunction, dilated cardiomyopa- population, but it is not yet widely available. thy, ST-T segment changes, atrial and ventricular Elevated transferrin saturation is usually the earli- est phenotypic expression of the disease1,5 - arrhythmias, and conduction abnormalities can oc- ; its sen sitivity for iron overload is 94% to 98%, with a cur.26 specificity of 70% to 98%.5 In the white popula- Pancreatic involvement, with beta cell damage tion, the sensitivity and specificity yield a positive and decreased insulin production, usually follows predictive value of approximately 20%, and a neg- liver involvement. The result can range from glu- ative predictive value of 99.9%. The test costs ap- cose intolerance to frank diabetes that requires in- proximately $20.35 sulin for control. There is also evidence of insulin Transferrin saturation is a calculated value (se- resistance in patients with hereditary hemochroma- rum iron divided by total iron-binding capacity) tosis, implying damage to insulin-responsive mech- that can be affected by other factors. If a screening 26,30 anisms. Although hemochromatosis can be the transferrin saturation is high, the test should be cause of diabetes, only a small percentage of dia- obtained after an overnight fast,18 as serum iron betic patients will be found to have hereditary levels can vary considerably after an oral dose.11,36 31 hemochromatosis. Clinical findings suggesting The iron-binding capacity is affected by acute and iron overload or liver disease in diabetic patients chronic disease states, oral contraceptives, and should prompt screening for iron overload. acute hepatitis.18 Normal transferrin saturation is

268 JABFP July–August 2001 Vol. 14 No. 4 J Am Board Fam Pract: first published as on 1 July 2001. Downloaded from http://www.jabfm.org/

Figure 1. Algorithm for evaluation of suspected hereditary hemochromatosis. If cirrhosis is present, consider periodic ␣-fetoprotein measurements and hepatic sonography. * Some authorities use 40 years as the age cutoff. on 24 September 2021 by guest. Protected copyright. † Positive indicates HFE gene test shows homozygous C282Y mutation. ‡ Negative indicates HFE gene test shows no mutation or mutation other than homozygous C282Y mutation. less than 45%, and elevations above this level war- monitor these values yearly.5 An elevated serum rant further evaluation. In men and postmeno- ferritin level defines the point at which treatment pausal women, transferrin saturations of 45% to should be initiated in patients with a confirmed 54% should be monitored at 1- to 2-year intervals.5 diagnosis.5 Serum ferritin is an acute phase reactant If the transferrin saturation exceeds 45% in pre- and can be elevated in the absence of iron overload. menopausal women or 55% in men and postmeno- Elevated levels of the serum ferritin generally occur pausal women, the workup should proceed with later in the course of iron overload than elevated determination of serum ferritin and hepatic enzyme transferrin saturation. For these reasons, serum fer- levels. ritin is less useful as an initial screening test for Serum ferritin concentration is linearly related hereditary hemochromatosis. to total body iron stores.5 Serum ferritin levels are Hepatic enzymes are useful to gauge the likeli- normally less than 300 ␮g/L in men and postmeno- hood of hepatic iron toxicity, but they are not pausal women, and less than 200 ␮g/L in premeno- useful as a screening tool.37 Studies have shown, pausal women.1 In patients with an elevated trans- however, that up to 3.4% of patients with elevated ferrin saturation but normal serum ferritin levels hepatic enzymes might have hereditary hemochro- and normal liver enzyme levels, it is prudent to matosis.29 Also, because concurrent hepatic toxins

Hereditary Hemochromatosis 269 accelerate the hepatic toxicity of iron overload, it is Table 2. Traditional Diagnostic Criteria for Hereditary recommended to screen for iron overload in pa- Hemochromatosis.

2 J Am Board Fam Pract: first published as on 1 July 2001. Downloaded from tients with evidence of liver disease. A. Observation of elevated transferrin saturation Ͼ60% on at Elevated serum ferritin or elevated hepatic en- least 2 occasions in the absence of other known causes of zyme levels in patients with an elevated fasting elevated transferrin saturation transferrin saturation indicate the need for further B. Diagnosis of iron overload: 1 plus 2, or 1 plus 3, below 1. Elevated serum ferritin not explained by another cause evaluation with HFE gene testing or liver biopsy. 2. Increased hepatic iron by either a or b, below HFE gene testing is readily available in the a. Increased stainable hepatocellular iron (Scheuer grade United States. The test is performed on a whole 3or4) specimen, and the cost to the patients is b. Increased hepatic iron concentration (Ͼ80 ␮mol/g) Ͼ about $180. A much less costly method for identi- and hepatic iron index ( 1.9) 38 3. Increased mobilizable iron (removal of4gofiron fying both mutations has recently been described. without development of iron-limited erythropoiesis) This lower cost test might eventually affect the role of genetic testing in both suspected persons and for Adapted from Witte, et al, Clinica Chimica Acta, 1996,29 and 5 general population screening. Currently, the ap- Powell et al, Annals of Internal Medicine 1998. propriate use of HFE gene testing is being debated and refined.5,6,19,26,39,40 HFE gene testing will not of less than 1,000 ␮g/L has also been shown to distinguish the 10% to 40% (depending on the predict the absence of liver fibrosis and is included population) of whites with non-HFE iron overload, in the decision process by some authorities.1,3,10,18 nor will it determine the cause of iron overload in Because liver disease itself can cause elevated most African-Americans or Asians.5 Thus, the HFE serum transferrin saturation and ferritin levels, bi- gene test is not recommended as a screening test opsy combined with HFE gene testing is often for iron overload. At present, one well-defined use necessary in patients with evidence of iron overload of HFE gene testing is to diagnose hereditary and suspected coexistent liver disease (such as viral hemochromatosis in relatives of patients who have hepatitis or ethanol-induced disease) to establish a a confirmed diagnosis. First-degree relatives should http://www.jabfm.org/ be screened with HFE gene testing to determine definitive diagnosis. In these cases HFE gene test- risk and need for further evaluation and treat- ing can confirm hereditary hemochromatosis as the 1,19,22,42 ment.1,2,22 cause of the iron overload and can help in In the pre-HFE testing era, liver biopsy was the risk stratification of family members. considered the reference standard for diagnosis of For patients who cannot or will not receive liver hereditary hemochromatosis, but this concept has biopsy, HFE gene testing should definitely be per- on 24 September 2021 by guest. Protected copyright. recently been challenged. Liver biopsy has a low formed. In these patients, serum markers of iron complication rate in properly selected patients. overload, in combination with homozygous C282Y Mortality ranges from 0.01% to 0.1%, and the risk mutation, are sufficient for the diagnosis and to of hemorrhage is 0.3%.18 The traditional criteria initiate treatment. For patients 30 to 40 years or for diagnosis based on hepatic iron stores are listed younger with no evidence of liver involvement and ␮ in Table 2. These criteria are not exclusive for serum ferritin levels of less than 1,000 g/L, a 22,23 hereditary hemochromatosis, as these levels of iron similar strategy is recommended. can be found in end-stage liver disease of other The diagnostic criteria for hereditary hemo- causes.2,41 Periportal iron deposition is usually seen chromatosis listed in Table 2 were developed in the in hereditary hemochromatosis as opposed to other pre-HFE gene testing era and thus do not include patterns of iron deposition in other disease states.1,5 HFE gene status. The availability of this technol- Liver biopsy establishes the presence and severity ogy will likely result in changes in these criteria in of iron overload as well as the presence or absence the foreseeable future. of hepatic fibrosis, which has important implica- One potential diagnostic criterion for hereditary tions for future evaluation.22 Some authorities state hemochromatosis (Table 2) is the finding of 4 g or that liver biopsy is not necessary in selected patients more of mobilizable iron (approximately 16 U of aged 30 to 40 years or younger with homozygous blood) through a weekly or biweekly phlebotomy C282Y defect and no laboratory or physical evi- schedule. Scheduled phlebotomy without inducing dence of liver disease.1,10,18,19 A serum ferritin level iron-limited erythropoiesis is considered diagnostic

270 JABFP July–August 2001 Vol. 14 No. 4 for parenchymal iron overload in lieu of tissue Erythropoietin therapy can be used for patients biopsy.5 with iron overload and hypoproliferative anemias, For patients showing evidence of iron overload such as in renal disease and anemia of chronic J Am Board Fam Pract: first published as on 1 July 2001. Downloaded from with heterozygous C282Y results, isolated H63D disease.9 In such cases with complicating hemato- homozygous mutations, or concurrent liver disease, poietic disease, balancing therapies can be difficult, liver biopsy and consultation with an expert can be and appropriate consultation is suggested. helpful in defining the cause of the problem.9,10 Iron chelation therapy is reserved for patients The role and method of population screening who are severely anemic.9,26 Deferoxamine is gen- are currently being debated. At present, the most erally well tolerated, but it has serious adverse side cost-effective general population screening test effects and is inconvenient and expensive.2,26 Oral might be the an unbound iron-binding capacity or agents are being investigated, but they are also transferrin saturation at age 20 to 30 years.1,2,12,35 associated with higher costs and undesirable side effects.2

Treatment Induction Phase The recommended treatment for most patients is Effective initial treatment requires removal of 5 to therapeutic phlebotomy.9 Therapeutic phlebotomy 20 g of iron for most patients.18 Each unit of whole includes an induction phase to induce iron deple- blood (500 mL) contains approximately 250 mg of tion and a maintenance phase (see below) to pre- iron.9,26 The frequency of phlebotomy depends on vent excess iron reaccumulation. Therapeutic phle- the severity of iron overload symptoms as well as botomy can be performed safely in the physician’s the patient’s overall state of health. For patients office or even in the patient’s home.9 Therapy with average or better body mass and evidence of should not be delayed until symptoms develop, as ongoing iron toxicity, aggressive treatment with the goal of therapy is to prevent irreversible organ twice weekly phlebotomy is indicated and generally damage.9,26 well tolerated.9 For those patients with iron over-

Care must be taken to assure optimal pre- and load and little or no evidence of toxicity, a less http://www.jabfm.org/ post-phlebotomy hydration.9 Precautions to avoid aggressive schedule of weekly or biweekly phlebot- postphlebotomy orthostatic hypotension should be omy is sufficient. Erythroid hyperplasia occurs after observed after each treatment. Adequate dietary a few weeks of treatment, which can permit accel- protein, vitamin B12, and folate intake should be eration of the treatment schedule in some pa- encouraged to support the accelerated erythropoi- tients.9,29 In general, because of sex differences and esis that occurs with therapy. For patients who find the effects of time on the extent of iron accumula- on 24 September 2021 by guest. Protected copyright. venipuncture uncomfortable, comfort can be en- tion, men require more phlebotomies than women, hanced by prescribing a topical anesthetic prepara- and older patients require more treatments than tion for use before each treatment. younger patients. Patients should be counseled to maintain a diet During the induction phase, most authorities with only moderate amounts of high–iron-content recommend that the hematocrit be measured be- foods.9 Iron supplementation in any form should be fore every other phlebotomy. For patients on a less strictly avoided. There is no reason to discourage aggressive treatment schedule, the hematocrit can vitamin C intake, with the exception of limiting be measured before every third or fourth treatment those patients who choose to take supplements to as long as the patient is asymptomatic.2 The target 500 mg/d.9,26 Ethanol should be avoided com- hematocrit during therapy is 35% to 40%.29 pletely in patients with liver disease.43 The serum ferritin level is the most reliable and Patients should be advised to avoid uncooked least expensive measure of the response to treat- seafood, because they have a unique susceptibility ment.9 Serum ferritin should generally be mea- to Vibrio vulnificus . Similarly, these pa- sured after each month of treatment until it falls tients are at increased risk of infection with this below 100 ␮g/L. Thereafter, it should be measured organism if they expose open wounds to warm after every other treatment.9 Iron depletion occurs coastal seawater. Therapeutic phlebotomy treat- when serum ferritin decreases to 20 to 50 ␮g/L or ment does not reduce susceptibility to V vulnificus when the hematocrit fails to rise above 33% for infection.9 more than 3 weeks after treatment.8,9,26,29

Hereditary Hemochromatosis 271 Maintenance Phase agnosis and treatment, before signs of iron toxicity, After completion of the induction phase, mainte- if possible, can result in improved quality and quan- nance therapy is required indefinitely to maintain tity of life for many patients. J Am Board Fam Pract: first published as on 1 July 2001. Downloaded from normal iron stores. This phase usually requires two to four phlebotomy sessions each year9 with a goal References of maintaining the serum ferritin level at less than 1. Press RD. Hereditary hemochromatosis: impact of 50 ␮g/L.26 molecular and iron-based testing on the diagnosis, treatment, and prevention of a common, chronic disease. Arch Pathol Lab Med 1999;123:1053–9. Response to Therapy 2. Powell LW, Subramaniam VN, Yapp TR. Haemo- Although the end points for the treating physician chromatosis in the new millennium. J Hepatol 1999; are easily measurable, the responses perceived by 32:48–62. the patient might not be so evident. Most patients 3. Adams PC. Population screening for haemochroma- report improvements in strength and pigmenta- tosis. Gut 2000;46:301–3. 4. McDonnell SM, Hover A, Gloe D, Ou CY, Cog- tion. Cardiomyopathy, if not severe, is likely to swell ME, Grummer-Strawn L. Population-based improve through the process of remodeling once screening for hemochromatosis using phenotypic the tissue toxin is removed. Hyperglycemia often and DNA testing among employees of health main- improves with treatment. Liver congestion and tenance organizations in Springfield, Missouri. Am J liver enzymes are likely to improve. Unfortunately, Med 1999;107:30–7. the arthritic symptoms, hypogonadism, and hypo- 5. Powell LW, George DK, McDonnell SM, Kowdley thyroidism do not improve with treatment.9 The KV. Diagnosis of hemochromatosis. Ann Intern Med 1998;129:925–31. endocrinopathies and arthritis caused by hereditary 6. Burke W, Thomson E, Khoury M, et al . Hereditary hemochromatosis might even continue to worsen hemochromatosis: gene discovery and its implication 7 despite treatment. Cirrhosis, if present, is not for population-based screening. JAMA 1998;280: likely to improve,29 although treatment might re- 172–8. sult in slowing the progression of cirrhosis in a few 7. McDonnell SM, Preston BL, Jewell SA, et al. A affected patients.9 Cirrhosis is the most reliable survey of 2,851 patients with hemochromatosis: http://www.jabfm.org/ predictor of survival. If there is no cirrhosis at the symptoms and response to treatment. Am J Med 1999;106:619–24. time of diagnosis, patients have a normal survival 8. Bacon BR, Schilsky ML. New knowledge of genetic with treatment. If cirrhosis is present, 5- and 10- pathogenesis of hemochromatosis and Wilson’s dis- year survivals with treatment are 72% and 62%, ease. Adv Intern Med 1999;44:91–116. 29 respectively. 9. Barton JC, McDonnell SM, Adams PC, et al. Man-

The most dreaded outcome of hereditary hemo- agement of hemochromatosis. Hemochromatosis on 24 September 2021 by guest. Protected copyright. chromatosis in patients with evidence of cirrhosis is Management Working Group. Ann Intern Med developing hepatocellular carcinoma.37 The risk of 1998;129:932–9. developing this cancer is as high as 19% if cirrhosis 10. Dooley JS, Walker AP. Genetic hemochromatosis: 20 detection, management, and population screening. is present, and 5% if cirrhosis is not present. Genet Test 2000;4(2):97–101. ␣ Many authorities recommend monitoring the -fe- 11. McDonnel SM, Phatak PD, Felitti V, Hover A, toprotein level or scheduling a hepatic sonogram McLaren GD. Screening for hemochromatosis in every 6 months for patients with cirrhosis, but primary care settings. Ann Intern Med 1998;129: effectiveness of this strategy is unclear.9,26,29 962–70. 12. McDonnell SM, Witte DL, Cogswell ME, McIntyre R. Strategies to increase detection of hemochroma- Conclusion tosis. Ann Intern Med 1998;129:987–92. Family physicians are likely to encounter patients 13. Andrews NC. Disorders of iron metabolism. N Engl with undiagnosed hereditary hemochromatosis in J Med 1999; 341:1986–95. their practices. Considering the prevalence of the 14. Hillman RS, Finch CA. Red cell manual. 7th ed. Philadelphia: F A Davis, 1996:71–3. disease, it is important for physicians to consider it 15. Feder JN, Penny DM, Irrinki A, et al. The hemo- in the differential diagnosis when patients complain chromatosis gene product complexes with the trans- of the common signs and symptoms. For most ferrin receptor and lowers its affinity for ligand bind- patients hereditary hemochromatosis can be suc- ing. Proc Natl Acad SciUSA1998;95:1472–7. cessfully treated in the physician’s office. Early di- 16. Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal

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Hereditary Hemochromatosis 273